Major depressive disorder is a debilitating mood disorder that affects ~7% of US adults in their lifetime, costing the U.S. economy more than $200 billion a year. Drugs that increase monoaminergic signaling are the mainstay of depression therapy, but have a delayed onset of action and are only effective in about 50% of affected patients. Aberrant brain-derived neurotrophic factor (BDNF) signaling has been proposed to underlie the pathophysiology of major depressive disorder and Bipolar disorder. We have developed a novel family of cyclic peptidomimetic compounds that potentiate the BDNF pathways to produce rapid (within hours) antidepressant effects. Here, we propose a Phase I proof-of- concept and feasibility study for the use of our patented new drug, CN2097, for treating depression. There are three major goals that focus on preclinical efficacy. Aim 1 will test the stability of CN2097 analogues and evaluate toxicity. Aim 2 will evaluate the rapid and long-term effects of treatment with CN2097 in mitigating depressive behaviors using two extensively validated models: Chronic mild stress (CMS) and Chronic social defeat stress (CSDS). Aim 3 will examine the ability of CN2097 to correct impairments in the cellular mechanisms of depression that include signaling, neuronal atrophy and synaptic plasticity.